Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

Abstract

SummaryThe first total synthesis of leopolic acid A, a fungal metabolite with a rare 2,3-pyrrolidinedione nucleus linked to an ureido dipeptide, was designed and carried out. Crucial steps for the strategy include a Dieckmann cyclization to obtain the 2,3-pyrrolidinedione ring and a Wittig olefination to install the polymethylene chain. An oxazolidinone-containing leopolic acid A analogue was also synthesized. The antibacterial activity showed by both compounds suggests that they could be considered as promising candidates for future developments.

One‐Step Synthesis of 3,4‐Diphenyl‐2‐pyrrolinones by Solvent‐Free and Bi2O3‐Catalyzed Approaches and Cytotoxicity Screening Against Glioma Cells

“…N-Butyl derivative 7 was the most active in the two glioma cell lines evaluated. As a general trend, all tested 2-pyrrolinones with two vicinal phenyl rings (3 and 6-8) were more active than those without this structural moiety (12)(13)(14). Apparently, the presence of a 2pyrrolinone core is not sufficient to be cytotoxic against tested cells, because the activity levels of 12-14 were comparable to those of 15 and 16 (Fig.…”

“…Cytotoxicity studies of δlactam in glioblastoma cells are scarce, and the unique example that caused a decrease in human glioblastoma cell survival was rolipram, 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone [50]. Thus, with a set of dihydro-2-pyrrolinones with (3-10) and without (12)(13)(14) two vicinal phenyl substituents prepared, the in vitro cytotoxicity against U251 and C6 glioma cells was investigated, in search of new potential antitumor activity of synthesized molecules. For comparative purposes, succinimide-enaminones 15 and 16 were evaluated as well.…”

“…3.70 (1H, dd, J 9.6 and 5.7 Hz), 3.01 (1H, dd, J 18 and 9.6 Hz), 2.75 (1H, dd, J 18 and 5.7 Hz), 2.10 (3H, s), 1.60 (1H, sl), 1.15 (3H, t). 13 Alternatively, a mixture of 41 mg (0.3 mmol) of enaminone 1a and 65 mg (0.3 mmol) of 11d was heated under reflux in toluene for 21 h and, after this time, was allowed to cool to room temperature and concentrated. The crude residue was recrystallized from a mixture of ethyl acetate and hexane, yielding 131 mg (76%) of 17, as a pale yellow solid, m.p.…”

“…The 2-pyrrolinone core is present in several compounds that possess interesting biological activities [1][2][3][4][5][6][7]. Because of this aspect, the synthesis of densely substituted 2pyrrolinone is a theme of ongoing interest, and the development of practical synthetic routes to access this heterocycle demands continuous improvements [8][9][10][11][12][13]. In a subclass of this δ-lactam, the occurrence of two vicinal phenyl substituents is a relevant structural scaffold because it increases the biological effect [1].…”

“…) 13. C-NMR (DMSO-D 6 , 75 MHz) δ 179.2, 169.6, 163.6, 153.9, 145.2, 142.1, 124.9, 118.7, 105.3, 58.9, 43.4, 36.0, 14.2, 13.5.…”